Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas
Makoto Yamagishi,
Makoto Hori,
Dai Fujikawa,
Takeo Ohsugi,
Daisuke Honma,
Nobuaki Adachi,
Harutaka Katano,
Tsunekazu Hishima,
Seiichiro Kobayashi,
Kazumi Nakano,
Makoto Nakashima,
Masako Iwanaga,
Atae Utsunomiya,
Yuetsu Tanaka,
Seiji Okada,
Kunihiro Tsukasaki,
Kensei Tobinai,
Kazushi Araki,
Toshiki Watanabe,
Kaoru Uchimaru
Affiliations
Makoto Yamagishi
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan; Corresponding author
Makoto Hori
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
Dai Fujikawa
Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Takeo Ohsugi
Department of Laboratory Animal Science, School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan
Daisuke Honma
Oncology Laboratories, Daiichi Sankyo, Co., Tokyo, Japan
Nobuaki Adachi
Biomarker Department, Daiichi Sankyo, Co., Tokyo, Japan
Harutaka Katano
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
Tsunekazu Hishima
Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
Seiichiro Kobayashi
Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Kazumi Nakano
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
Makoto Nakashima
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
Masako Iwanaga
Department of Clinical Epidemiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Atae Utsunomiya
Department of Hematology, Imamura General Hospital, Kagoshima, Japan
Yuetsu Tanaka
Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan
Seiji Okada
Joint Research Center for Human Retrovirus Infection, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Kunihiro Tsukasaki
Department of Hematology, International Medical Center, Saitama Medical University, Saitama, Japan
Kensei Tobinai
Department of Hematology, National Cancer Center Hospital, Tokyo, Japan
Kazushi Araki
Oncology Clinical Development Department, Daiichi Sankyo Co., Tokyo, Japan
Toshiki Watanabe
Future Center Initiative, The University of Tokyo, Tokyo, Japan
Kaoru Uchimaru
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan; Corresponding author
Summary: Although global H3K27me3 reprogramming is a hallmark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2WT/WT has yet been established. We explore epigenome and transcriptome in EZH2WT/WT and EZH2WT/Mu aggressive lymphomas and show that mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange their own genome-wide distribution, thereby establishing restricted chromatin and gene expression signatures. Direct comparison of leading compounds introduces potency and a mechanism of action of the EZH1/2 dual inhibitor (valemetostat). The synthetic lethality is observed in all lymphoma models and primary adult T cell leukemia-lymphoma (ATL) cells. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. Inactivation of chromatin-associated genes (ARID1A, SMARCA4/BRG1, SMARCB1/SNF5, KDM6A/UTX, BAP1, KMT2D/MLL2) and oncovirus infection (HTLV-1, EBV) trigger EZH1/2 perturbation and H3K27me3 deposition. Our study provides the mechanism-based rationale for chemical dual targeting of EZH1/2 in cancer epigenome. : A mechanism-based, effective strategy for controlling oncogenic H3K27me3 remains an open question. Yamagishi et al. provide the scientific rationale for dual targeting of EZH1+EZH2 in malignancies overexpressing EZH2, such as ATL, PTCL, and DLBCL, or harboring mutations in histone-modifying genes, as well as in pre-cancerous cells epigenomically perturbed by oncovirus infection. Keywords: EZH1, EZH2, H3K27me3, epigenetic drug, malignant lymphoma, adult T cell leukemia-lymphoma (ATL), HTLV-1, polycomb
